Smoking and the skin

Cigarette smoking has been associated with significant morbidity affecting all systems of the body, including the integumentary system. We review the many dermatologic hazards of tobacco use. It is important to distinguish between the effects of tobacco smoke from effects of pure nicotine on the skin. All skin cells express several subtypes of the nicotinic class of acetylcholine receptors, including the α7 receptor. Many chronic dermatoses are affected by smoking either negatively or positively. Elucidation of positive associations with a particular disease can lead to improvement from smoking cessation, whereas inverse correlation may lead to development of a disease-specific treatment with nicotinergic agonists.     

Establishment of a choriocarcinoma model from immortalized normal extravillous trophoblast cells transduced with HRASV12

Gestational choriocarcinoma is a malignant trophoblastic tumor. The development of novel molecular-targeted therapies is needed to reduce the toxicity of current multiagent chemotherapy and to treat successfully the chemoresistant cases. The molecular mechanisms underlying choriocarcinoma tumorigenesis remain uncharacterized, however, and appropriate choriocarcinoma animal models have not yet been developed. In this study, we established a choriocarcinoma model by inoculating mice with induced-choriocarcinoma cell-1 (iC3-1) cells, generated from HTR8/SVneo human trophoblastic cells retrovirally transduced with activated H-RAS (HRASV12). The iC3-1 cells exhibited constitutive activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and developed into lethal tumors in all inoculated mice. Histopathological analysis revealed that the tumors consisted of two distinct types of cells, reminiscent of syncytiotrophoblasts and cytotrophoblasts, as seen in the human choriocarcinoma. The tumors expressed HLA-G and cytokeratin (trophoblast markers) and hCG (a choriocarcinoma marker). Comparative analysis of gene expression profiles between iC3-1 cells and parental HTR8/SVneo cells revealed that iC3-1 cells expressed matrix metalloproteinases, epithelial-mesenchymal transition-related genes, and SOX3 at higher levels than parental trophoblastic cells. Administration of SOX3-specific short-hairpin RNA decreased SOX3 expression and attenuated the tumorigenic activity of iC3-1 cells, suggesting that SOX3 overexpression might be critically involved in the pathogenesis of choriocarcinoma. Our murine model represents a potent new tool for studying the pathogenesis and treatment of choriocarcinoma.     

Indocyanine green fluorescence imaging in the pregnant cynomolgus macaque: childbearing is supported by a unilateral uterine artery and vein alone?

Purpose

Uterine blood flow is required for the maintenance of uterine viability in pregnancy and delivery, but it is unknown how many vessels are necessary for maintenance of uterine viability. The objective of this study was to examine whether unilateral uterine vessels provide sufficient nutrition in pregnancy in a cynomolgus macaque and to evaluate hemodynamics of pregnant uterus by indocyanine green (ICG) fluorescence imaging.

Methods

A cynomolgus macaque with uterine blood flow maintained by the right uterine artery and vein alone was made pregnant. Hemodynamics of the uterus in the third trimester was evaluated by ICG fluorescence imaging.

Results

Pregnancy was maintained with the right uterine artery and vein. An appropriate-for-date infant was delivered by Cesarean section. ICG fluorescence imaging showed that the uterine body was imaged from the right side to the center; furthermore, collateral circulation was present from the right uterine artery toward the left uterine artery, with expanded blood flow to the left uterine body.

Conclusion

Pregnancy and delivery were achieved in a cynomolgus macaque with a unilateral right uterine artery and vein. Blood flow to the side without the artery was complemented by vascularization of collateral circulation to the uterine artery.     

Complex genomic rearrangement in the SOX9 5' region in a patient with Pierre Robin sequence and hypoplastic left scapula

Pierre Robin sequence (PRS) can occur as a component of campomelic dysplasia (CD) and acampomelic CD (ACD) caused by dysfunction or dysregulation of SOX9, although it can also take place as an isolated form. Recently, genomic alterations in the far upstream and the far downstream region of SOX9 have been identified in patients with isolated PRS. Here, we report on a male patient with PRS and a heterozygous genomic rearrangement in the 5' region of SOX9. Clinical analysis revealed PRS-compatible craniofacial anomalies, mild hypoplasia of the left scapula, and normal male external genitalia. Molecular analysis identified a paracentric inversion on the long arm of chromosome 17 with breakpoints at 17q21.31 and 17q24.3, and a microdeletion spanning from -4.15 to -1.16?Mb relative to SOX9. These findings indicate that the chromosomal region more than 1.16?Mb apart from SOX9 contains at least one developmental enhancer(s) for SOX9 that plays a critical role in the development of the mandible and a relatively small role in the development of the scapula. Moreover, the concept of exclusion mapping argues that putative CD/ACD loci are located within the 1.16?Mb region closest to SOX9 coding exons, which remain intact in this Non-CD/ACD patient. This study provides a novel example for long-range cis-regulatory mutations of SOX9.     

Gastrointestinal stromal tumor in the duodenum exhibiting hemangiopericytoma-like histological pattern

Reported herein is a gastrointestinal stromal tumor (GIST) that exhibited a hemangiopericytoma (HPC)-like histological pattern. Such a morphological variant of GIST has not been described previously. A 57-year-old woman presented with bloody stools. On upper digestive tract endoscopy a submucosal tumor of diameter 2 cm was detected at the duodenal bulb, and enucleated. Grossly, the tumor was well-circumscribed, grayish to whitish, and solid, and its central portion was ulcerated. Histology indicated round to fusiform tumor cells that had proliferated around branching vessels that had a staghorn configuration. Immunohistochemistry showed that the tumor cells were diffusely positive for vimentin and KIT; partially positive for CD34 and muscle actin; and negative for α-smooth muscle actin. On mutation analysis a 42 bp deletion was found from codons 560 to 573 of exon 11 of the KIT gene, which is a mutational hot spot of GIST. In diagnosis of gastrointestinal tract tumors with an HPC-like histological pattern, pathologists should consider the possibility of GIST.     

IFN-{gamma} expression in CD8+ T cells regulated by IL-6 signal is involved in superantigen-mediated CD4+ T cell death

Infection with pathogens containing superantigens (Sags) canresult in massive excessive CD4⁺ T cell activation and deathin such conditions as toxic shock, food poisoning and autoimmunediseases. We here showed how enhancement of IL-6 signaling suppressesSag-mediated activated CD4⁺ T cell death. Sag-induced CD4⁺ Tcell death increased in IL-6 knockout (KO) mice, whereas itdecreased in mice characterized by enhanced IL-6–gp130–STAT3signaling. The serum concentration of IFN- was inversely correlatedwith the magnitude of IL-6 signaling, and IFN- deficiency inhibitedSag-induced activated CD4⁺ T cell death, suggesting that IL-6suppresses CD4⁺ T cell death via IFN- expression. Interestingly,depletion of activated CD8⁺ T cells inhibited Sag-mediated increasesin IFN- expression in IL-6 KO mice as well as the augmentedCD4⁺ T cell death. The results demonstrate that IL-6–gp130–STAT3signaling in activated CD8⁺ T cells contributes to Sag-inducedCD4⁺ T cell death via IFN- expression, highlighting this signalingaxis in CD8⁺ T cells as a potential therapeutic target for Sag-relatedsyndromes.     

Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases

Background

Bone-modifying agents are effective for treatment of breast cancer patients with bone metastases. Since their action is mediated through suppression of the osteoclast function, their efficacy can be determined by monitoring bone turnover markers. However, the clinical significance of these markers is yet to be compared.

Methods

For this study, 52 breast cancer patients with bone metastases treated with zoledronic acid (n = 36) or denosumab (n = 22) were enrolled (6 patients were treated sequentially with both agents). Serum tartrate-resistant acid phosphatase-5b (TRACP-5b), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP), N-terminal cross-linking telopeptides of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) were measured at pretreatment and 1, 3 and 6 months after treatment.

Results

Serum TRACP-5b (p < 0.0001), NTX (p = 0.0007) and BAP (p = 0.0032) decreased significantly after treatment. The baseline median value of TRACP-5b (457.5 mU/dL, range 173–1630 mU/dL) decreased to 137 mU/dL (91–795 mU/dL) 1 month after treatment. Reduction in serum NTX and BAP was greatest after 3 and 6 months, respectively. TRACP-5b, NTX and BAP were above normal levels at baseline in 62.5, 25 and 35.3 % of patients, respectively, and nearly 80 % of these patients attained normal levels during the treatment.

Conclusions

Although bone-modifying agents reduced the baseline levels of TRACP-5b, NTX and BAP significantly, the reduction patterns differed. TRACP-5b appears to affect levels most quickly and sensitively, possibly due to its direct link to the number and activity of osteoclasts. These findings suggest that the efficacy of TRACP-5b is clinically significant when considering which bone-modifying agents to use for breast cancer patients with bone metastases.